J H Dodd, C F Schwender, J B Moore, D M Ritchie, Y Gray-Nunez, D Loughney, T Kirchner, W C Miller, S Mockoviak
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引用次数: 0
Abstract
A series of cyclic sulfone dihydropyridines ranging in sulfone ring size from five to nine membered have been evaluated for calcium antagonist activity. Increasing the sulfone ring size from 5 to 8 membered resulted in a two orders of magnitude in vitro potency increase. Aromatic substitution which favored tracheal effects over aortic effects was found to be 2-NO2 and 2-Cl, 6-F. The ester side chain which was found to maximize in vivo activity was the N-benzyl-N-methyl aminoethyl moiety. Combination of all these structural features resulted in RWJ 22108, a bronchoselective calcium channel blocker which preclinically exhibits an antiasthmatic profile.
一系列的环砜二氢吡啶在砜环大小从5到9个成员已经评估了钙拮抗剂的活性。砜环由5元增加到8元，体外效价提高2个数量级。芳香取代对气管的影响大于对主动脉的影响，发现2-NO2和2-Cl, 6-F更有利。体内活性最高的酯侧链是n -苄基- n -甲基氨基乙基部分。所有这些结构特征的结合导致了rwj22108，一种支气管选择性钙通道阻滞剂，临床前表现出平喘的特征。
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